DESCRIPTION: IGFIR and IGFII are antiapoptotic, growth-stimulatory receptor-ligand pair that play an important role in human tumorigenesis. The hypothesis of this proposal is that at least a subset of gastrointestinal tumorigenesis relies on IGFIR signal transduction to prevent apoptosis, and that inhibition of IGFIR signaling will cause cancer cells to undergo apoptosis. In addition, the P.I. hypothesizes that IGFII-catabolizing protein, the IGFII receptor (IGFIIR), is a growth-suppressive component of the IGFIR signaling pathway whose inactivation advances tumor growth. Finally the P.I. states that primary tumors will exhibit reciprocal alterations in p53 and IGFIR or its pathway components, and that these alterations have an effect on the biologic aggressiveness of gastrointestinal tumors. The specific aims of the proposal are: To test agents that effectively and specifically block signaling through the IGFIR with the final goal to augment apoptosis induced by chemotherapeutic regimens. To determine the involvement of IGFIIR in the IGFIR growth axis both in vitro and in primary gastrointestinal tumors in vivo To correlate IGFIR and IGFIIR expression and function with p53 status and clinical outcome in primary human gastrointestinal tumors in vivo.